For the past quarter century, Dr. Raju Kucherlapati has been a driving force in advancing our understanding of human genetics and their potential applications in medicine. A professor at at Harvard Medical School, he has spearheaded landmark initiatives like the Human Genome Project and the ongoing Cancer Genome Atlas Program, redefining what is possible in genetic research and cancer treatment.
We had the opportunity catch up with Dr. Kucherlapati at the BIOHK 2024 conference in Hong Kong for a fascinating — and encouraging — conversation about what future holds for some exciting frontiers in medicine. Here, Dr. Kucherlapati talks about the many advancements being made in genome sequencing, the rise of precision medicine, and its transformative global impact.
Dr. Raju Kucherlapati and Donglei Mao, the Editor-in-Chief of PharmaDJ at BIOHK 2024.
Q: Dr. Kucherlapati, can you tell us a bit about your background and your involvement in the Human Genome Project?
Dr. Kucherlapati: I am a professor of genetics and medicine at Harvard Medical School, and I also hold appointments at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston. I was fortunate to be part of the Human Genome Project, which began in 1990. Our mission was to map and sequence the entire human genome, a monumental task that initially started as a collaboration between the U.S. and with more countries joining as the project progressed. While we completed the mapping and sequencing of the genome in 2003, the cost of sequencing remained very high at that time.
The U.S. government, recognizing this, challenged the scientific and business communities to find innovative ways to reduce the cost of genome sequencing. Back in 2001, sequencing a single human genome cost around $2.5 billion. However, thanks to tremendous advances in technology over the past two decades, we’ve reduced that cost to about $300. This has allowed the global community, including countries like China, to sequence hundreds of thousands of human genomes, greatly expanding our understanding of human genetics.
Q: What impact did the Human Genome Project have on the development of precision medicine?
Dr. Kucherlapati: The completion of the Human Genome Project was a turning point. It gave rise to the field of precision medicine, where we use genetic information to tailor medical treatments to individual patients. One area where this has had a significant impact is in cancer research. In the U.S., cancer is one of the leading causes of death, second only to heart disease, and by understanding the genetic mutations that drive cancer, we can develop more effective, personalized treatments. This effort was furthered by the launch of the Cancer Genome Atlas Program (TCGA) in 2006, which I’ve been a part of since its inception. Through this program, we’ve been able to sequence tumor DNA and gain deeper insights into how cancer works. The program is ongoing and involves multiple laboratories around the world, working together to improve cancer care.
Q: You mentioned precision medicine. Can you elaborate on its current state and the related challenges, such as cost-effectiveness, access to advanced technologies, and data privacy concerns? What does the landscape of precision medicine look like in the U.S. and globally?
Dr. Kucherlapati: Precision medicine is advancing rapidly, particularly in countries like the U.S., where it is transforming how we diagnose and treat diseases. However, there are still significant challenges we need to address. One key issue is cost-effectiveness. Although the price of genome sequencing has dropped dramatically, implementing precision medicine on a large scale requires substantial investment in infrastructure, technology, and expertise. Additionally, access to advanced technologies, such as genomic sequencing and personalized treatment options, is not yet equitable. Many regions, particularly in low-income countries, face barriers to adopting these innovations, which can exacerbate global healthcare disparities.
Another major challenge is data privacy and security. Precision medicine relies heavily on vast amounts of genetic and health data. Ensuring the confidentiality of this data while also facilitating research is a delicate balance. We need robust legal and ethical frameworks to protect individuals' genetic information from misuse while still allowing the scientific community to leverage this data for research and advancements in care.
Q: Where is precision medicine currently making the most significant impact, especially throughout the human life cycle?
Dr. Kucherlapati: Precision medicine is impacting various stages of life, from prenatal care to old age. For example, in prenatal care, genetic testing has become a crucial tool, especially for women over the age of 35, who are at a higher risk of having children with certain genetic conditions. In such cases, fetal genetic testing is often recommended. One method used is amniocentesis, where a small sample of amniotic fluid is taken from the uterus to extract fetal DNA. This allows us to screen for genetic abnormalities early in pregnancy, enabling parents and healthcare providers to make informed decisions.
As we move through life, precision medicine continues to play a role. In oncology, it helps us understand the genetic makeup of tumors, enabling us to design treatments that target the specific mutations driving cancer in an individual. It is also making strides in treating rare genetic disorders and improving preventative healthcare, where we can identify an individual’s genetic predisposition to certain diseases and intervene early.
Q: Is it difficult to obtain fetal DNA through traditional methods?
Dr. Kucherlapati: Traditionally, yes. Amniocentesis, which is commonly used, is an invasive procedure where a needle is inserted through the abdomen to collect amniotic fluid. This procedure can be uncomfortable, and in some cases, it carries risks and is expensive. However, an important breakthrough occurred when it was discovered that a portion of fetal DNA circulates in the mother’s bloodstream. Now, with non-invasive prenatal testing (NIPT), we can detect fetal DNA simply by taking a small blood sample from the mother. It’s a straightforward process, similar to a routine blood test. Most pregnant women over 35 now undergo this test to screen for certain genetic conditions. This advancement has revolutionized prenatal care and the prevention of hereditary diseases.
Q: That’s fascinating! How has DNA testing impacted care for infants and children?
Dr. Kucherlapati: The impact has been profound. Each year, millions of children are born, and about 5% have detectable genetic conditions. In the past, diagnosing these diseases was often a lengthy and challenging process. But with rapid DNA sequencing, we can now quickly and accurately diagnose genetic disorders in newborns. This advancement has not only improved diagnostic capabilities but has also paved the way for targeted treatments. Diseases that were once considered untreatable now have promising therapies.
For example, cystic fibrosis, a condition that affects the lungs and digestive system, used to be untreatable because we didn’t know its genetic cause. Now, thanks to advances in genetic research and precision medicine, there are effective drugs available globally, including in China. Similarly, new treatments are being developed for other childhood disorders, some of which were once deemed incurable. As a result, children with these conditions are living longer, healthier lives.
Q: Could you give us an example of how precision medicine is contributing to drug development?
Dr. Kucherlapati: Harvard Medical School, where I teach, is deeply involved in drug development, collaborating with biotech and pharmaceutical companies from the early discovery stages. Precision medicine plays a crucial role in this process by enabling the development of targeted therapies. One example is sickle cell anemia, a genetic condition where blood cells become sickle-shaped, leading to serious health problems. Although this disease has been known for a long time, no effective treatment existed until recently. In 2023, the FDA approved a new drug for sickle cell anemia, made possible by our deepened understanding of the genetics behind the disease.
This is just one example, but many more diseases that were once untreatable are now being addressed with new therapies. Another area where precision medicine is making an impact is cancer treatment.
Q: Speaking of cancer, how has the Cancer Genome Atlas Program influenced cancer research and treatment?
Dr. Kucherlapati: The Cancer Genome Atlas Program, which began in 2006, was a major turning point in cancer research. Initially, tumors were classified based on their location — lung cancer, breast cancer, brain cancer, and so on. However, by studying the genetic mutations that drive these cancers, we can now classify tumors much more precisely. Instead of thinking about lung cancer as a single disease, we now know it can be caused by different mutations in various genes. This genetic understanding has led to the development of targeted therapies that address specific mutations.
For instance, 20 years ago, lung cancer had very limited treatment options. But today, in 2024, there are more than 100 targeted drugs available for lung cancer alone, giving patients a better chance of long-term survival. Beyond targeted therapies, there’s been significant progress in immunotherapy, such as PD-1 and CTLA-4 inhibitors. These treatments help the body’s immune system fight cancer more effectively, though not all patients respond to them. Now, by sequencing the DNA of tumor biopsies, we can determine whether a patient is more likely to benefit from immunotherapy or a different targeted approach.
Q: When we talk about cancer treatment, a major issue is drug resistance. Could you explain more about that?
Dr. Kucherlapati: Drug resistance is a significant challenge in cancer treatment. Patients often go through multiple lines of treatment — first-line, second-line, and sometimes even fourth-line therapies. However, these treatments don’t always work for every patient. In some cases, patients may initially respond well to a drug, but over time, the cancer can develop resistance, making the treatment ineffective. This is where precision medicine and sequencing technology have the potential to make a real difference in the future.
When treating cancer, it’s crucial to know early on whether the treatment is working. If the therapy isn’t effective, it’s important to adjust the treatment strategy quickly. One key approach to monitoring treatment success is through measuring what’s known as 'minimal residual disease' (MRD). MRD refers to the small number of cancer cells that might remain in the patient after treatment. If we can detect these remaining cells, we can determine whether the cancer is responding to the treatment or if resistance is developing.
Q: How do you monitor minimal residual disease (MRD) and how does this tie into precision medicine?
Dr. Kucherlapati: Monitoring MRD has become more precise with the use of liquid biopsies, a non-invasive method where we take a small blood sample from the patient. By analyzing the blood, we can detect whether any cancer cells remain. This allows us to see whether a patient is responding well to the treatment or if the cancer is developing resistance. Liquid biopsies provide real-time insights into the patient’s condition without needing more invasive procedures like traditional biopsies.
This ability to track the cancer’s behavior enables doctors to adjust the treatment strategy if needed. For example, if we see signs that the treatment isn’t working, we can switch to a different drug or a different therapeutic approach before the cancer becomes too advanced.
Precision medicine is all about tailoring treatment to the individual. With tools like liquid biopsies and MRD monitoring, we can now sequence and match the right drugs to each patient based on their unique genetic profile. This approach ensures that patients receive treatments that are most likely to be effective for their specific cancer type and genetic mutations.
In the past, we didn’t have the ability to fine-tune treatment in this way. But now, with these diagnostic tools and advancements in sequencing technology, we can make much more informed decisions. This is still a relatively new field, but it holds tremendous potential to improve cancer care.
As we discussed earlier, innovations like personalized vaccines, which target specific genetic mutations in a patient’s tumor, and the ability to test the efficacy of existing drugs in real-time, are truly transformative. Our goal is to increase the effectiveness of cancer treatments, reduce the likelihood of drug resistance, and improve the overall care and survival rates for patients.
We are indeed in the early stages of applying many of these innovative technologies. Numerous new companies are emerging that focus on cutting-edge methods like liquid biopsies. There’s considerable hope that these companies can translate their innovations into clinical practice, making a real difference in patient care.
Q: You mentioned cancer vaccines. Could you explain their role in cancer treatment?
Dr. Kucherlapati: Cancer vaccines represent an exciting new frontier. There are two categories of cancer vaccines: preventative vaccines, like the HPV vaccine, which helps prevent cervical cancer, and therapeutic vaccines, which are designed to treat existing cancer. Therapeutic vaccines are personalized, meaning they are developed based on the specific genetic mutations found in a patient’s tumor. By identifying these mutations, we can create vaccines that target those precise changes, helping the immune system recognize and attack cancer cells.
These vaccines aren’t just about preventing cancer; they’re designed to prevent recurrence and to help treat existing cancer more effectively. This approach, enabled by precision medicine, represents the future of cancer treatment. As we continue to understand the genetic underpinnings of various cancers, we will see more personalized therapies and vaccines that offer hope to patients.
Q: Beyond cancer treatment, how else can precision medicine be applied?
Dr. Kucherlapati: Precision medicine has a wide range of applications that extend throughout the human life cycle. It starts with pregnancy, where it can support expectant mothers and monitor fetal health. As children grow into adolescents and eventually adults, precision medicine continues to play a critical role in their healthcare. For instance, I’ve previously discussed how precision medicine benefits pregnant women, children, and adults, especially in cancer treatment, but its applications reach far beyond these areas.
This is an exciting development, as precision medicine is crucial for the future of healthcare.
Q: What role do government and private investment companies play in advancing precision medicine?
Dr. Kucherlapati: The government plays a vital role in advancing precision medicine, but private investment is equally essential. Venture capital firms can support new biotech companies, particularly in regions like Hong Kong, Shenzhen, and Guangzhou, which are becoming biotech hubs similar to those in the United States.
Private investment fosters innovation in this field, enabling startups to explore and develop groundbreaking technologies.
Q: How can we ensure that healthcare professionals are equipped to implement these advancements?
Dr. Kucherlapati: Educating young doctors in hospitals and universities about these exciting developments is crucial. They need to understand how precision medicine can benefit their patients; without this knowledge, they won’t be able to implement these advancements effectively.
Conferences like HIOHK or CMAC are significant because they bring together diverse stakeholders — government officials, private investors, academics, and biotech professionals. By fostering collaboration and sharing knowledge, we can better equip healthcare providers and promote the integration of precision medicine into clinical practice.
Q: How important is public awareness and government investment in this area?
Dr. Kucherlapati: Educating the public is essential. We must encourage and promote government investment in precision medicine. By reporting on and sharing advancements in this field, we can raise awareness about the technologies available and their potential impact on healthcare.
Highlighting success stories, such as companies that have developed drugs for diseases like cystic fibrosis or innovative gene therapies, illustrates the tangible benefits of investing in precision medicine. This can inspire further support from both the public and private sectors.
Q: Are there challenges we need to consider, particularly regarding healthcare reimbursement?
Dr. Kucherlapati: Absolutely. While there are numerous examples of how we can advance precision medicine, we must also consider healthcare reimbursement. Precision medicine can be quite costly, and the prices for these treatments may rise. It’s critical to address these financial aspects to ensure that patients can access the innovative therapies being developed.
Let’s consider the example of sickle cell disease, which illustrates the complexity of treatment costs. Currently, many individuals with this condition suffer significantly and often require regular blood transfusions to manage their symptoms.
If a single blood transfusion costs around $10,000 per year and a person lives for 50 years, that adds up to $500,000 over their lifetime. If they live for 80 years, the costs increase even further, resulting in potentially devastating financial burdens on both patients and healthcare systems.
Q: How does this compare to new treatment options available for sickle cell disease?
Dr. Kucherlapati: Now, let’s contrast that with a new treatment that costs $100,000 but is administered only once in a lifetime. While some may view this one-time treatment as expensive, it’s important to frame it in the context of the ongoing costs associated with managing the disease over many years. From a long-term perspective, this one-time treatment could ultimately be more cost-effective.
It underscores the necessity of reevaluating our approach to treatment costs in the context of long-term patient care. By shifting our focus from immediate expenses to the overall lifetime costs of managing chronic conditions, we can develop more sustainable healthcare policies that ensure access to innovative therapies while controlling expenses.
Q: How can we ensure that all stakeholders recognize the importance of treatment outcomes?
Dr. Kucherlapati: It’s critical to inform all stakeholders about the significance of patient outcomes. They need to understand that when patients are treated with specific therapies, the results can be markedly beneficial. Government support for outcomes research is vital in this regard.
During my tenure as an advisor at the Centers for Medicare and Medicaid Services (CMS) in the U.S., I worked on educating them and other stakeholders about these emerging technologies and their potential benefits. As a major national insurance agency, CMS's approach to reimbursement can set a precedent; when they acknowledge the value of these treatments, private insurance companies are likely to follow suit.
Q: Now, I would like to shift the focus to emerging technologies. What are your thoughts on the future of gene editing technologies, like CRISPR-Cas9, in precision medicine?
Dr. Kucherlapati: Gene editing holds great promise for precision medicine. A notable development is the approval of a drug in 2023 that utilizes CRISPR technology, marking a significant milestone. However, it’s important to consider the intellectual property issues surrounding CRISPR in the U.S. I'm less familiar with the situation in Hong Kong and China, but these concerns will undoubtedly influence the progression of gene editing technologies.
However, licensing requirements are a significant barrier; anyone wishing to use CRISPR must obtain a license, which can be costly. This has prompted efforts to create alternative technologies that don’t carry such fees. Innovations in CRISPR therapy and cell therapy are becoming more accessible, and as advancements continue, we can expect a rise in the development of drugs utilizing these technologies. In fact, my research indicates that China has over 50 companies focusing on gene therapy with CRISPR-Cas9, suggesting they are catching up to the U.S. in this field.
Q: What about the regulatory and ethical considerations associated with these technologies?
Dr. Raju Kucherlapati: Regulatory and ethical frameworks are critical. In the U.S., the FDA plays a key role in overseeing these advancements. They have committed to supporting companies developing cell-based and gene therapies by providing guidance documents that clarify the development process.
Moreover, the FDA reviews protocols from smaller companies and offers constructive feedback to ensure they meet regulatory requirements while prioritizing safety and efficacy. Ethical considerations are paramount, too. It’s essential to establish transparent frameworks for clinical trials, informed consent, and equitable access to therapies. Regulatory bodies must also consider the long-term implications of gene editing technologies, such as unintended consequences and moral considerations.
Fostering collaboration among these entities is vital for the responsible development of groundbreaking therapies. In many cases, companies can work closely with regulatory agencies, which can provide support throughout the drug development process.
In Hong Kong, discussions are underway about establishing an independent regulatory agency, as advocated by the Chief Executive. Such an agency could not only review data but also collaborate in designing clinical trials that prioritize safety and efficacy.
Q: In addition to being a professor at Harvard Medical University, you also established your own company as CEO. Could you share your thoughts on the differences between being a scientist and being an entrepreneur, particularly in the context of running a company?
Dr. Kucherlapati: Certainly! As a scientist, my primary responsibility is to develop innovative ideas that can lead to valuable intellectual property. I use this intellectual property to attract investors and initiate new companies. Once a company is established, it typically has its own CEO, Chief Scientific Officer, and other key personnel. My role during this phase is often that of a founder, where I concentrate on generating ideas and securing the necessary funding to bring them to life.
After the company is set up, I may take on various roles. I can serve on the board of directors, where I offer guidance and strategic oversight. Additionally, I might be part of the scientific advisory committee, or I may fulfill both responsibilities simultaneously.
Q: As a professor, what do you believe is the most important aspect of your role?
Dr. Kucherlapati: While becoming a professor typically involves publishing significant research in reputable journals, I believe the most important aspect is the ability to help fellow human beings. That’s what truly excites me about my work and motivates my contributions to the field.
Every individual can make a meaningful contribution. If many people do their part, the collective impact can be significant. Educating students and doctors is a vital step in this process.
Q: I know you are one of the speakers at the CBA in China. You've been very enthusiastic about promoting collaboration between these two countries, despite the current tense relationship. What is your goal in sharing opportunities for collaboration?
Dr. Kucherlapati: There are numerous ways to foster collaboration between China and the U.S. For example, in 2017, I co-chaired an advisory committee for constructing a new cancer hospital in China. We aimed to establish it as a precision medicine facility. I brought together a team of experts from the U.S. to provide guidance throughout the process, and I'm pleased to say the hospital is now operating successfully. To further this collaboration, we decided to organize an annual conference, rotating its location across different regions of China.
The Chinese Biopharmaceutical Association - USA (CBA) Conference is a prominent international event organized by the CBA, bringing together top Chinese professionals in the global biopharmaceutical industry to explore the latest developments, challenges, and opportunities in biopharmaceutical technology. Founded in 1995 and headquartered in Maryland, CBA is a nonprofit organization comprised of individuals involved in biopharmaceutical research, regulatory affairs, and professional management. Its members represent various sectors, including R&D and regulatory agencies.
The CBA is committed to fostering cooperation and exchange among Chinese biopharmaceutical professionals worldwide. The conference covers a wide range of topics, including basic research, clinical development, commercialization, and regulatory policies. It serves as a platform for sharing international perspectives, discussing cutting-edge advancements, promoting industry collaboration, and enhancing professional networking within the biopharmaceutical field.
Q: That sounds impressive! Where have these conferences been held?
Dr. Kucherlapati: We've hosted meetings in cities such as Tianjin, Shenzhen, Chongqing, and Haikou, rotating the venue each year.
Q: That’s interesting. How has your perspective on China's healthcare evolved since your first visit?
Dr. Kucherlapati: I first came to China about 10 or 12 years ago, and my impressions were striking. During my visits to large hospitals in cities like Shanghai, Beijing, Tianjin, Shenzhen, and Guangzhou, I found many of them on par with the best in the world. However, I also encountered smaller hospitals that were less advanced—more akin to secondary or tertiary facilities. The contrast between these institutions was quite memorable for me.
Q: Do you see a commitment to improvement in those smaller hospitals?
Dr. Kucherlapati: Yes, there's a strong dedication to improvement. One initiative to foster this change involves sending Chinese doctors to the United States to learn best practices in healthcare. For example, this month, I’m hosting a meeting for a group of 10 doctors from Henan in Boston. I’ve arranged visits to seven different hospitals for them to gain insights into various practices and technologies.
Q: How does this engagement extend to other organizations?
Dr. Kucherlapati: I work closely with my friend Susan, the president of the Asian Fund for Cancer Research. She has established a partnership with the City University of Hong Kong, which invited me to contribute to their recent meeting. I helped design the program for this part of the conference and invited colleagues from the U.S. to participate.
Just yesterday, professors from the U.S. visited City University and met with their counterparts there. These exchanges foster personal connections and collaboration, illustrating that despite geopolitical differences, we can still build meaningful relationships.
Q: What motivates you to host these tours and engage with China?
Dr. Kucherlapati: My motivation stems from a genuine desire to understand how different countries and cultures operate. When I first visited China many years ago, I was truly amazed by the rapid development of infrastructure, such as impressive highways and modern buildings. Witnessing such swift evolution and improvement has left a lasting impression on me. In our discussions about hospitals, I see that while some facilities are exceptional, others certainly could benefit from support. I find it incredibly rewarding to interact with and contribute to this progress.
Q: What challenges do you face when collaborating with China and what are your expectations for the U.S. and Chinese governments regarding collaboration in life sciences?
Dr. Raju Kucherlapati: The key is to work only with those who are genuinely interested in collaboration. Everyone I partner with has been enthusiastic, creating a positive environment. I’ve been fortunate to have great experiences; the people I've met both in the U.S. and China have been incredibly kind and open to cooperation.
I hope for a more open and collaborative environment in the life sciences. Despite regulatory challenges and geopolitical tensions, it's crucial to prioritize scientific collaboration and mutual benefit. Innovations in medicine and technology often thrive on shared knowledge and partnerships.
Q: Your insights truly capture the essence of collaboration across cultures. What final thoughts do you have on this matter?
Dr. Kucherlapati: Building personal relationships can bridge divides and foster understanding, even amidst political differences. By bringing people together, like my efforts in showcasing Hong Kong BioHK and CBA, we’re helping create a more interconnected world. It’s heartening to see individuals taking proactive steps to strengthen these ties.